PROJECT SUMMARY The specific focus of this phase I application is to develop liver tissue-targeting histone deacetylase inhibitors (HDACi) for targeted hepatocellular carcinoma (HCC) therapy. HCC accounts for over 80% of all liver cancers and is one of the most common types of malignancies. HCC is associated with a relatively low 5-year survival rate, and it is the third leading cause of cancer death globally. Surgical resection, the common treatment option, is limited to those patients with good liver function and early stage disease. Unfortunately, only a small proportion of patients are suitable candidates for surgery, and the relapse rate is very high after surgery. Liver transplant has proven successful in treating limited cases of early stage HCC as only an even smaller proportion of patients are eligible for transplantation. Systemic chemotherapy is considered to offer the most promise in the treatment of HCC. This promise became closer to reality with the FDA approval of sorafenib in 2007. However, sorafenib extends survival in advanced HCC patients by 7.9 to 10.7 months. Therefore, there continues to be an unmet medical need for safe and efficacious HCC therapeutic strategies. HCC is a complex and heterogeneous neoplasm as it results from a large number of genetic mutations and epigenetic alterations. In particular, gene-silencing chromatin histone hypoacetylation play a significant role in the development and sustenance of HCC; therefore, novel compounds endowed with a histone deacetylase (HDAC) inhibitory activity are attractive HCC therapeutic agents. Our hypothesis is that selective accumulation of HDACi within diseased tissues will enhance the therapeutic indices of HDACi and expand their efficacy to include solid tumors. Toward this end, we seek to develop new HDACi which selectively accumulate in liver tissues as clinically useful targeted anti-HCC agents. Our specific aims are: 1) Develop liver targeted HDACi as novel anticancer agents against HCC. 2) Advance liver targeted HDACi through characterization of the structural and biochemical requirements for whole cell and in vivo efficacy of lead compounds in mice. We believe that a successful implementation of the proposed studies will furnish a new class of targeted anti- HCC agents and provide a foundation for the initiation of comprehensive ADMET studies during the Phase II grant period that will ultimately enable Sophia Bioscience file an Investigational New Drug (IND) application preparatory to human clinical trials.